Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California.
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
Am J Physiol Renal Physiol. 2022 Oct 1;323(4):F411-F424. doi: 10.1152/ajprenal.00067.2022. Epub 2022 Aug 18.
While angiotensin-converting enzyme (ACE) regulates blood pressure by producing angiotensin II as part of the renin-angiotensin system, we recently reported that elevated ACE in neutrophils promotes an effective immune response and increases resistance to infection. Here, we investigate if such neutrophils protect against renal injury in immune complex (IC)-mediated crescentic glomerulonephritis (GN) through complement. Nephrotoxic serum nephritis (NTN) was induced in wild-type and NeuACE mice that overexpress ACE in neutrophils. Glomerular injury of NTN in NeuACE mice was attenuated with much less proteinuria, milder histological injury, and reduced IC deposits, but presented with more glomerular neutrophils in the early stage of the disease. There were no significant defects in T and B cell functions in NeuACE mice. NeuACE neutrophils exhibited enhanced IC uptake with elevated surface expression of FcγRII/III and complement receptor CR1/2. IC uptake in neutrophils was enhanced by NeuACE serum containing elevated complement C3b. Given no significant complement activation by ACE, this suggests that neutrophil ACE indirectly preactivates C3 and that the C3b-CR1/2 axis and elevated FcγRII/III play a central role in IC elimination by neutrophils, resulting in reduced glomerular injury. The present study identified a novel renoprotective role of ACE in glomerulonephritis; elevated neutrophilic ACE promotes elimination of locally formed ICs in glomeruli via C3b-CR1/2 and FcγRII/III, ameliorating glomerular injury. We studied immune complex (IC)-mediated crescentic glomerulonephritis in NeuACE mice that overexpress ACE only in neutrophils. Such mice show no significant defects in humoral immunity but strongly resist nephrotoxic serum nephritis (less proteinuria, milder histological damage, reduced IC deposits, and more glomerular neutrophils). NeuACE neutrophils enhanced IC uptake via increased surface expression of CR1/2 and FcgRII/III, as well as elevated serum complement C3b. These results suggest neutrophil ACE as a novel approach to reducing glomerulonephritis.
虽然血管紧张素转换酶 (ACE) 通过产生血管紧张素 II 作为肾素-血管紧张素系统的一部分来调节血压，但我们最近报道，中性粒细胞中 ACE 的升高可促进有效的免疫反应并提高对感染的抵抗力。在这里，我们研究了这种中性粒细胞是否通过补体来保护免疫复合物 (IC)-介导的新月体性肾小球肾炎 (GN) 中的肾脏免受损伤。在过表达中性粒细胞 ACE 的野生型和 NeuACE 小鼠中诱导肾毒性血清肾炎 (NTN)。与 NeuACE 小鼠相比，NTN 中的肾小球损伤减轻，蛋白尿减少，组织学损伤较轻，IC 沉积减少，但在疾病早期有更多的肾小球中性粒细胞。NeuACE 小鼠的 T 和 B 细胞功能没有明显缺陷。NeuACE 中性粒细胞表现出增强的 IC 摄取，表面表达 FcγRII/III 和补体受体 CR1/2 增加。含有升高的补体 C3b 的 NeuACE 血清增强了中性粒细胞的 IC 摄取。鉴于 ACE 没有显著激活补体，这表明中性粒细胞 ACE 间接预激活 C3，并且 C3b-CR1/2 轴和升高的 FcγRII/III 在中性粒细胞消除 IC 中起核心作用，导致肾小球损伤减少。本研究确定了 ACE 在肾小球肾炎中的一种新的肾保护作用；升高的中性粒细胞 ACE 通过 C3b-CR1/2 和 FcγRII/III 促进局部形成的 IC 在肾小球中的消除，从而改善肾小球损伤。我们研究了仅在中性粒细胞中过表达 ACE 的 NeuACE 小鼠中的免疫复合物 (IC)-介导的新月体性肾小球肾炎。这种小鼠的体液免疫没有明显缺陷，但强烈抵抗肾毒性血清肾炎（蛋白尿减少、组织学损伤较轻、IC 沉积减少、肾小球中性粒细胞增多）。NeuACE 中性粒细胞通过增加表面表达的 CR1/2 和 FcgRII/III 以及升高的血清补体 C3b 来增强 IC 摄取。这些结果表明中性粒细胞 ACE 是减少肾小球肾炎的一种新方法。
